Odour character differences for enantiomers correlate with molecular flexibility

Abstract

The olfactory system sensitively discerns scents from many small molecules as the brain analyses signals from nasal receptors. These receptors are selective to some degree, though the mechanism for selectivity is still controversial. Enantiomers, chiral pairs of left- and right-handed structures, are an important class of molecules in assessing proposed mechanisms. We show that there is a correlation between molecular (structural) flexibility and whether or not the left- and right-handed enantiomers smell the same. In particular, for the fairly extensive class of enantiomers with six-membered ring flexibility, enantiomers do not smell the same. There are, of course, significant experimental uncertainties, which we discuss here. We discuss models of receptor selectivity, both those based on shape and those where discrimination is based on other factors, such as electron affinity, proton affinity or vibration frequencies. The differences in scent of these enantiomers appear to be consistent with simple generalizations of a 'swipe card' model in which, while the shape must be good enough, critical information for actuation is a separate factor.

Figure 1

An odorant square representing in shades odorant classifications, within the strong regime, where type 1 is 5%. The bottom-left corner represents type 1, the top-right corner type 2, along the x-axis represents type 1c and along the y-axis represents type 1i. Graduations in shade are meant to indicate areas of ambiguity and show an overlap between the four categorizations. While graduated areas are contentious, we note that all examples examined in this paper are taken from odorants that lie within one of the corners. In other words, where it may be disputable how enantiomer pairs may smell different from one another, it is not disputable whether they smell the same or whether they smell different.

Figure 2

Type 2 cis- and trans-p-menthan-8-thiol-3-ones. (a) (1S,4R)-cis smells ‘blackcurrant leaf, tropical note of passion fruit, intensive fruit note’. (1R,4S)-cis smells ‘rubber, mercaptan note, isopulegone note, sulphurous, disagreeable’. (b) (1R,4R)-trans smells ‘onion-like, weak fruity, tropical, dirty’. (1S,4S)-trans smells ‘stronger than (1R,4R)-isomer, tropical, sulphurous, pronounced buchu leaf oil notes’.

Figure 3

Type 2 (a) chair and (b) boat (1R)-γ-methyl cyclogeranate smells ‘camphoraceous, corky, cellar’ and (1S)-γ-methyl cyclogeranate smells ‘aromatic, damascone-like, thujone, fruity’.

Figure 4

Type 2 (a) equatorial and (b) axial (4R)-(−)-carvone smells ‘sweet spearmint, fresh herbal’ and (4S)-(+)-carvone smells ‘caraway, fresh herbal’.

Figure 5

Cyclohexane simulation of 20 ps, showing the conformational space of an isolated gas-phase molecule at (a) 600 K, (b) 300 K and (c) 10 K. We note that with increasing temperature, cyclohexane explores a much wider conformational space: at 600 K, more heavily populating pseudorotating states between boat and twist.

Figure 6

Cyclohexane simulation of 100 ps, showing the conformational space of an isolated gas-phase molecule at (a) 600 K, (b) 300 K and (c) 10 K. We note that after the 20 ps equilibration at higher temperatures, cyclohexane will easily surmount the energy barrier and heavily populate pseudorotating states between boat and twist, throughout a longer simulation.

Figure 7

(a) Cyclohexane, (b) (4R)-(−)-carvone (type 2) and (c) (1R,4S)-(+)-fenchone (type 1) at 600 K. The simulations ran for 20 ps. We clearly note that cyclohexane reaches the boat–twist pseudorotating barrier, (4R)-(−)-carvone approaches it, but (1R,4S)-(+)-fenchone does not.

Figure 8

(a) Cyclohexane, (b) (4R)-(−)-carvone (type 2) and (c) (1R,4S)-(+)-fenchone (type 1) at 600 K. The simulations ran for 100 ps. We clearly note that cyclohexane easily reaches the boat–twist pseudorotating barrier, as does (4R)-(−)-carvone, but (1R,4S)-(+)-fenchone even after a longer simulation does not.

Figure 9

Type 1i, (a) (4R,4aR,8aS)-(+)-geosmin and (b) (4S,4aS,8aR)-(−)-geosmin smell ‘earthy, musty’.

Figure 10

Type 1, (a) (4R,4aS,6R,8aS)-(+)-tetrahydronootkatone and (b) (4S,4aR,6S,8aR)-(−)-tetrahydronootkatone smell ‘dusty-woody, fresh, green, sour, spicy, herbal, slightly fruity, animal, erogenic’.

Figure 11

Type 2, nootkatones: (a) (4R,4aS,6R)-(+)-nootkatone smells of grapefruit (0.8 ppm) and (b) (4S,4aR,6S)-(−)-nootkatone is ‘woody, spicy’ (600 ppm) (Bentley 2006). Note also that the (+) enantiomer is approximately 750 times more potent than the (−) enantiomer (Eliel & Wilen 1993).

Figure 12

Type 1, (4R,4aS,6R,8aS)-(+)-tetrahydronootkatone, 600 K simulation for 100 ps. This odorant does not reach the pseudorotating contour as shown in cyclohexane (figure 6). It is not flexible.

Figure 13

Type 2, (4R,4aS,6R)-(+)-nootkatone, 600 K simulation for 100 ps. This odorant does reach the pseudorotating contour as shown in cyclohexane (figure 6). It is flexible.

Figure 14

Type 1i, (a) (4R,4aR,8aS)-(+)-geosmin and (b) (4S,4aS,8aR)-(−)-geosmin: ESP fit to the electron density isosurface. Note that there is one main region of electronegativity, corresponding to the ‘osmophoric group’.

Figure 15

Type 1, (a) (4R,4aS,6R,8aS)-(+)-tetrahydronootkatone and (b) (4S,4aR,6S,8aR)-(−)-tetrahydronootkatone: ESP fit to the electron density isosurface. Note that there is one main region of electronegativity.

Figure 16

Type 2, (a) (4R,4aS,6R)-(+)-nootkatone and (b) (4S,4aR,6S)-(−)-nootkatone: ESP fit to the electron density isosurface: note that there are two main regions of negativity, one weaker than the other.

Figure 17

Type 1, (a) (5R)- and (b) (5S)-10-demethyl-β-vetivone smells ‘intense cresolic’.